ClinVar

Silvestri et al. (1994) described a C-to-T transition at nucleotide 3303 of mtDNA in 7 members of a family with cardiomyopathy and skeletal myopathy. The proband and 2 sibs had fatal infantile cardiomyopathy, whereas in 3 maternal relatives the disease manifested later in life as sudden cardiac death or as mitochondrial myopathy with cardiomyopathy. The mutation was homoplasmic in all tissues (including blood) from the proband and her brother, but heteroplasmic in blood from 5 oligosymptomatic or asymptomatic maternal relatives. The mutation disrupted a conserved basepair in the aminoacyl stem of the tRNA-leu (UUR).

The causative role of the 3303C-T mutation in the MTTL1 gene was confirmed by Bruno et al. (1999), who found the mutation in 8 patients from 4 unrelated families. In the first family, the clinical presentation was infantile cardiomyopathy; in the second family, proximal limb and neck weakness dominated the clinical picture for the first 10 years of life, when cardiac dysfunction became apparent; in the third family, 2 individuals presented with isolated skeletal myopathy and 2 others with skeletal myopathy and cardiomyopathy; in the fourth family, 1 patient had fatal infantile cardiomyopathy and the other had a combination of skeletal myopathy and cardiomyopathy.